This invention pertains to a method of treatment for inhibiting the spread of malignant cells, or metastasis.
"Metastasis", as used herein, is defined as the transfer of malignant tumor cells, or neoplasm, via preformed body vascular channels (blood vessels or lymphatics), or via natural body cavities, usually from the primary focus of neoplasia to a distant site in the body, and subsequent development of secondary tumors or colonies in the new location.
Metastasis is an ominous sign of malignancy and often represents a significant factor leading to death. Its treatment is difficult to achieve with conventional methods, such as surgery and radiotherapy. Efforts to treat cells in metastasis by a systematic therapy, such as the one proposed in this application, have heretofore been largely unsuccessful.
The mechanism by which metastasis occurs is believed to involve several steps, such as entry of tumor cells into the circulation (intravasculation); their transport by the blood stream; interactions of circulating malignant cells with platelets and plasma clotting factors with activation of the hemostatic system; interaction of the same cells with host cells other than platelets; arrest of tumor cells, surrounded by platelet aggregates and fibrin clots within capillaries; proteolytic attack of the blood vessel wall, particularly of its basement membrane, by tumor enzymes; escape from the circulation system (extravasculation); and formation of secondary tumors or colonies.
Blood sucking animals, such as leeches, mosquitoes and vampire bats have long been known to possess in their saliva substances which chemically interact with the blood or blood components. For this reason, leeches have been used for blood letting since antiquity. Although this practice achieved great popularity in Europe at the beginning of the last century and has since been abandoned, interest in the nature and properties of leech anticoagulants (one of the known components of the leech saliva which react with blood clotting factors) has recently been renewed as a consequence of the greater interest in the biochemistry of blood clotting and the search for new antithrombotic agents. These investigations have culminated in the isolation and characterization of several leech anticoagulants, such as hirudin, a specific thrombin inhibitor from the species Hirudo medicinalis; hementerin, a plasminogen activator from leeches of the species Haementeria lutzi, and hementin, a fibrinogen and fibrin degrading enzyme from leeches of the species Haementeria ghilianii and probably from leeches of the species Haementeria officinalis.
Studies of the salivary glands from Hirudo or Haementeria leeches have also revealed the presence of several kind of protease inhibitors, i.e., substances capable of neutralizing or inhibiting the degrading or digestive activity of proteins by conventional enzymes, such as trypsin, plasmin, chymotrypsin, elastase, cathepsins, etc.
With regard to possible use as antimetastatic agents, conventional anticoagulants, including heparin and Bothrops atrox venom (Atroxin); antiplatelet agents, such as aspirin; and inhibitors of proteolytic activity from various natural sources, such as leupetin, aprotinin, etc. have all been tested and studied (individually). And some of these agents have shown a marginal (but only marginal) capacity to inhibit metastatic activity.
Notwithstanding these studies, however, there remains a continuing need for a more effective antimetastatic treatment method.
It is the general object of the present invention to provide such a method.
More specifically, an object of this invention is to provide a method of treatment to inhibit metastasis, by administering a therapeutically effective amount of a composition apparently uniquely adapted to inhibit metastasis.